TPM2

Chr 9AD

tropomyosin 2

Also known as: AMCD1, CMYO23, CMYP23, DA1, DA2B, DA2B4, HEL-S-273, NEM4

NCBI Gene: 7169ENSG00000198467UniProt: P07951

This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

Primary Disease Associations & Inheritance

Arthrogryposis, distal, type 1AMIM #108120
AD
Arthrogryposis, distal, type 2B4MIM #108120
AD
Congenital myopathy 23MIM #609285
AD
444
ClinVar variants
118
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TPM2
🧬
Gene-Disease Validity (ClinGen)
TPM2-related myopathy · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
118 Pathogenic / Likely Pathogenic· 140 VUS of 444 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.83LOEUF
pLI 0.000
Z-score 2.12
OE 0.47 (0.28–0.83)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.13Z-score
OE missense 0.52 (0.43–0.62)
80 obs / 154.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.47 (0.28–0.83)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.52 (0.43–0.62)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 9 / 19.0Missense obs/exp: 80 / 154.7Syn Z: -0.19

ClinVar Variant Classifications

444 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic78
Likely Pathogenic40
VUS140
Likely Benign147
Benign23
Conflicting16
78
Pathogenic
40
Likely Pathogenic
140
VUS
147
Likely Benign
23
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
5
70
0
78
Likely Pathogenic
7
18
15
0
40
VUS
5
88
46
1
140
Likely Benign
0
1
90
56
147
Benign
0
0
23
0
23
Conflicting
—16
Total1511224457444

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TPM2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TPM2-related arthrogryposis, distal

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
TROPOMYOSIN 2; TPM2
MIM #190990 · *

Arthrogryposis, distal, type 1A

MIM #108120

Molecular basis of disorder known

Autosomal dominant

Arthrogryposis, distal, type 2B4

MIM #108120

Molecular basis of disorder known

Autosomal dominant

Congenital myopathy 23

MIM #609285

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Congenital myopathies: pathophysiological mechanisms and promising therapies.
Zhang H et al.·J Transl Med
2024Review
[Congenital myopathies].
Cabello A et al.·Rev Neurol
2003Review
A pathogenic mechanism associated with myopathies and structural birth defects involves TPM2-directed myogenesis.
McAdow J et al.·JCI Insight
2022Functional
Tropomyosins in skeletal muscle diseases.
Kee AJ et al.·Adv Exp Med Biol
2008Review
Probing long COVID through a proteomic lens: a comprehensive two-year longitudinal cohort study of hospitalised survivors.
Gu X et al.·EBioMedicine
2023Cohort
Tropomyosin isoforms encoded by TPM2 control the actin-bundling activity of fascin-1.
Siatkowska M et al.·Biol Res
2025
A Cross-Sectional Study of Nemaline Myopathy.
Amburgey K et al.·Neurology
2021
Myopathies associated with β-tropomyosin mutations.
Tajsharghi H et al.·Neuromuscul Disord
2012Review
Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) 2B and mild DA in two Chinese families.
Li S et al.·BMC Med Genet
2018
A recurrent pathogenic variant in TPM2 reveals further phenotypic and genetic heterogeneity in multiple pterygium syndrome-related disorders.
Vogt J et al.·Clin Genet
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools